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Background: Aldosterone-producing adenoma (APA) is a benign adrenal tumor with autonomous aldosterone production which causes hypertension and excess cardiovascular risk. Protein phosphorylation regulates aldosterone secretion from adrenal cortical cells, but how signaling networks are remodeled in APA remains unknown. Methods: We performed an integrated proteomic and phosphoproteomic profiling of 15 APA and 10 matched nonfunctioning adrenocortical tumors (NFAT) based on the 4-dimensional label-free technique. We further validated our main findings in enlarged APA samples, mice, and adrenocortical cell line. Results: The proteomic and phosphoproteomic profiling of APA and NFAT quantified 5989 proteins and 9011 phosphopeptides. We highlighted differentially expressed and phosphorylated proteins which modulated aldosterone synthesis and secretion from APA. As intracellular calcium is the central signal for aldosterone synthesis, our integrated calcium signaling network implicated wolframin in the control of calcium influx and CYP11B2 (aldosterone synthase) activation in APA (ratio of wolframin expression in APA to NFAT: 6.411, P Conclusions: Wolframin is a regulatory protein in aldosterone hypersecretion. Remodeled calcium transportation and mitochondrial function are involved in wolframin-related aldosterone secretion.

Gold-silica drug nanocapsules were fabricated via peptide photowrapping, which respond to an MMP-upregulated tumor microenvironment and achieve chemo-photothermal combination therapy.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) are a network structure composed of loose chromatin and embedded with multiple proteins. Here, we observed increased NETs deposition in the glomeruli of DKD patients and diabetic mice (streptozotocin-induced or db/db mice). After NETs were degraded with DNase I, diabetic mice exhibited attenuated glomerulopathy and glomerular endothelial cells (GECs) injury. We also observed alleviated glomerulopathy and GECs injury in peptidylarginine deiminase 4–knockout mice with streptozotocin-induced diabetes. In vitro, NETs-induced GECs pyroptosis was characterized by pore formation in the cell membrane, dysregulation of multiple genes involved in cell membrane function, and increased expression of pyroptosis-related proteins. Strengthening the GECs surface charge by oleylamine significantly inhibited NETs-induced GECs pyroptosis. These findings suggest that the GECs charge-related pyroptosis is involved in DKD progression, which is promoted by NETs.

A series of

Fluoxetine (FLX), used in the clinic to treat depression, is a well-known cationic amphiphilic antidepressant. However, there is a lack of research on the effect of FLX on the surface behavior of lipid monolayers under different surface pressures. In this study, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/CHOL (DPPC/POPC/CHOL) monolayers were prepared via the Langmuir method, and FLX was added to these monolayers under various surface pressures. The effect of FLX on the surface behavior of DPPC/POPC/CHOL monolayers under various surface pressures was studied using a combination of surface pressure-area isotherms, compressibility modulus-surface pressure curves, and atomic force microscope (AFM). The results showed that the effect of FLX on the lipid monolayers was different under different surface pressures. The interaction between FLX and lipid molecules was weak under low surface pressures, and FLX could easily intercalate between the lipid molecules to inhibit monolayer phase transition. The interaction between FLX and lipid molecules was enhanced and FLX tended to self-aggregate to reduce the monolayer stability when the surface pressure was high. This study lays the foundation for further studies on the interaction between FLX and lipid monolayers.

Current guidelines recommend adrenal venous sampling (AVS) to identify unilateral primary aldosteronism (UPA) before offering adrenalectomy. However, AVS is costly and technically challenging, limiting its use to expert centres.To establish a model to predict UPA, and therefore, bypass the need for AVS prior to surgery.The model was developed in a Chinese cohort and validated in an Australian cohort. Previously published prediction models of UPA were also tested.primary aldosteronism patients with a definite subtyping diagnosis based on AVS and/or surgery.Diagnostic value of the model.In the development cohort (268 UPA and 88 bilateral primary aldosteronism), combinations of different levels of low serum potassium (≤3.0 or 3.5 mmol/l), high PAC (≥15-30 ng/dl), low PRC (≤2.5-10 μIU/ml) and presence of unilateral nodule on adrenal CT (8-15 mm in diameter) showed specificity of 1.00 and sensitivity of 0.16-0.52. The model of serum potassium 3.5 mmol/l or less, PAC at least 20 ng/dl, PRC 5 μIU/ml or less plus a unilateral nodule at least 10 mm had the highest sensitivity of 0.52 (0.45-0.58) and specificity of 1.00 (0.96-1.00). In the validation cohort (84 UPA and 117 bilateral primary aldosteronism), the sensitivity and specificity of the model were 0.13 (0.07-0.22) and 1.00 (0.97-1.00), respectively. Ten previous models were tested, and only one had a specificity of 1.00 in our cohorts but with a very low sensitivity [0.07 (0.04-0.10) and 0.01 (0.00-0.06) in our development and validation cohorts, respectively].A combination of high PAC, low PRC, low serum potassium and unilateral adrenal nodule could accurately determine primary aldosteronism subtype in 13-52% of patients with UPA and obviate the need for AVS before surgery.

Group I chitin deacetylases (CDAs), CDA1 and CDA2, play an essential role in cuticle formation and molting in the process of insect wing development. A recent report showed that trachea are able to take up a secreted CDA1 (serpentine, serp) produced in the fat body to support normal tracheal development in the fruit fly Drosophila melanogaster. However, whether CDAs in wing tissue were produced locally or derived from the fat body remains an open question. To address this question, we applied tissue-specific RNAi against DmCDA1 (serpentine, serp) and DmCDA2 (vermiform, verm) in the fat body or the wing and analyzed the resulting phenotypes. We found that repression of serp and verm in the fat body had no effect on wing morphogenesis. RT-qPCR showed that RNAi against serp or verm in the fat body autonomously reduced their expression levels of serp or verm in the fat body but had no non-autonomous effect on the expression in wings. Furthermore, we showed that inhibition of serp or verm in the developing wing caused wing morphology and permeability deficiency. Taken together, the production of Serp and Verm in the wing was autonomous and independent of the fat body.

BackgroundArterial stiffness is a significant determinant and evaluation of cardio-cerebrovascular disease and all-cause mortality risk in the stroke population. Estimated pulse wave velocity (ePWV) is a well-established indirect measure of arterial stiffness. We examined the association of ePWV with all-cause and cardio-cerebrovascular disease (CCD) mortality in the stroke population in a large sample of US adults.MethodsThe study design was a prospective cohort study with data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2014, between the ages of 18–85 years, with follow-up through December 31, 2019. 1,316 individuals with stroke among 58,759 participants were identified and ultimately, 879 stroke patients were included in the analysis. ePWV was calculated from a regression equation using age and mean blood pressure according to the following formula: ePWV = 9.587 − (0.402 × age) + [4.560 × 0.001 × (age2)] − [2.621 × 0.00001 × (age2) × MBP] + (3.176 × 0.001 × age × MBP) − (1.832 × 0.01 × MBP). Survey-weighted Cox regression models were used to assess the association between ePWV and all-cause and CCD mortality risk.ResultsThe high ePWV level group had a higher increased risk of all-cause mortality and CCD mortality compared to the low ePWV level group after fully adjusting for covariates. With an increase in ePWV of 1 m/s, the risk of all-cause and CCD mortality increased by 44%–57% and 47%–72% respectively. ePWV levels were linearly correlated with the risk of all-cause mortality (P for nonlinear = 0.187). With each 1 m/s increase in ePWV, the risk of all-cause mortality increased by 44% (HR 1.44, 95% CI: 1.22–1.69; P < 0.001). When ePWV was P < 0.001) increase in CCD mortality risk; when ePWV was ≥12.1 m/s, an increase in ePWV per 1 m/s was not associated with in CCD mortality risk.ConclusionePWV is an independent risk factor for all-cause and CCD mortality in stroke patients. Higher levels of ePWV are associated with higher all-cause mortality and CCD mortality in stroke patients.

To evaluate the steady-state availability of heterogeneous edge computing-enabled wireless sensor networks (HECWSNs) with malware infections, we first propose a Stackelberg attack-defence game to predict the optimal strategies of malware and intrusion detection systems (IDSs) deployed in heterogeneous sensor nodes (HSNs). Next, we present a new malware infection model—heterogeneous susceptible-threatened-active-recovered-dead (HSTARD) based on epidemic theory. Then, considering the heterogeneity of sink sensor nodes and common sensor nodes and the malware attack correlation, we derive the state transition probability matrix of an HSN based on a semi-Markov process (SMP), as well as the steady-state availability of an HSN. Furthermore, based on a data flow analysis of HSNs, we deduce the steady-state availability of HECWSNs with various topologies, including the star topology, cluster topology, and mesh topology. Finally, numerical analyses illustrate the influence of the IDS parameters on the optimal infection probability of malware and reveal the effect of multiple factors on the steady-state availability of HSNs, including the initial infection rate, the infection change rate, and the malware attack correlation. In addition, we present data analyses of the steady-state availability of HECWSNs with various topologies, including the star topology, cluster topology, and mesh topology, which provide a theoretical basis for the design, deployment, and maintenance of high-availability HECWSNs.

BackgroundEstimated pulse wave velocity (ePWV) has been proposed as a potential alternative to carotid-femoral pulse wave velocity to assess the degree of aortic stiffness, and may predict cardiovascular disease (CVD) outcomes and mortality in the general population. However, whether arterial stiffness estimated by ePWV predicts all-cause and cause-specific mortality in patients with diabetes mellitus (DM) has not been reported.MethodsThis was a prospective cohort study with data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014 and followed up until the end of December 2019. 5,235U.S. adults with DM (age≥20years) were included in the study. Arterial stiffness was estimated by ePWV. Survey-weighted Cox proportional hazards models were performed to assess the hazard ratios (HRs), and 95% confidence intervals (CIs) for the associations of ePWV with all-cause and cause-specific mortality. Meanwhile, the generalized additive model was used to visually assess the dose-dependent relationship between ePWV and mortality. As a complementary analysis, the relationship between mean blood pressure (MBP) and risk of mortality was also examined. Multiple imputations accounted for missing data.ResultsFor the 5,235 DM patients, the weighted mean age was 57.4 years, and 51.07% were male. During a median follow-up period of 115 months (interquartile range 81-155 months; 53,159 person-years), 1,604 all-cause deaths were recorded. In the fully adjusted Cox regression model, every 1 m/s increase in ePWV was associated with 56% (HR 1.56; 95% CI, 1.44 to 1.69) increase in the risk of all-cause. In addition, a nonlinear relationship between ePWV and all-cause mortality was observed (P for non-linear=0.033). Similar results were obtained after subgroup analysis and multiple imputations. Besides, the risk of most cause-specific mortality, except for accident and renal disease-specific mortality, increased from 53% to 102% for every 1 m/s increase in ePWV.ConclusionsIn the diabetic population, ePWV is independently associated with all-cause and most cause-specific mortality risks. ePWV may be a useful tool for assessing mortality risk.

The deposition of lignin and carbohydrates in different cells and morphologically distinct cell wall layers during the development of Calamus simplicifolius was investigated by combined microscopic techniques. Lignin autofluorescence images showed that protoxylem vessels were the first to differentiate among vascular elements. At the subcellular level, high spatial resolution Raman images revealed that the deposition of carbohydrates in fibers preceded that of lignin. Additionally, the lignin and carbohydrates concentration in the secondary wall (SW) varied among different cell types. The carbohydrates concentration in SW of fibers presented the highest level, which was much higher than that in vessels and parenchyma. High concentrations of lignin were most visible in the SW of vessels, followed by fibers, with the lowest amount visible in parenchyma. Within the morphologically distinct cell wall layers, the carbohydrates and lignin in fibers SW and cell corners deposited rapidly at the early stage from the 7th to the 10th internode, while the deposition rate decreased from the 10th to the 50th internode. The findings have substantial theoretical significance to understand the biosynthesis of rattan cell walls.

Boron (B) deficiency is an agricultural problem that causes significant yield losses in many countries. B transporters (BORs) are responsible for B uptake and distribution and play important roles in yield formation. A comprehensive analysis of the BOR family members in common wheat is still lacking. In the present study, to clarify the molecular characterization and response to B status, genome-wide TaBOR genes and expression patterns were investigated. Fourteen TaBOR genes were identified in common wheat by a homology search. The corresponding phylogenetic tree indicated that 14 TaBOR genes were separately classified into subfamilies of TaBOR1, TaBOR3, and TaBOR4. All TaBOR genes had 12–14 extrons and 11–13 introns. Most TaBOR proteins contained 10 conserved motifs, and motifs 1, 2, 3, 4, and 6 constituted the conserved bicarbonate (HCO3–) domain. Fourteen TaBOR genes were mapped on 13 chromosomes mainly distributed in the first, third, fifth, and seventh homologous groups. The promoters of TaBOR genes consisted of phytohormones, light responses, and stress-related cis-elements. GO analysis indicated that TaBOR genes were enriched in terms of transmembrane transport and ion homeostasis. TaBOR genes showed diverse expression profiles in different tissues. The members of the TaBOR1 subfamily showed high expression in grains, leaves, roots, stems, and spikes, but members of the TaBOR4 subfamily were highly expressed only in spikes and grains. RT–qPCR indicated that TaBOR1-5A, TaBOR1-5B, and TaBOR1-5D were induced by low B concentrations and had much higher expression in roots than in shoots. TaBOR3-3A, TaBOR3-3B, TaBOR3-3D, TaBOR4-1A, TaBOR4-1B, TaBOR4-1D, and TaBOR3-4B were induced by low and high B concentrations and had high expression in roots and shoots. TaBOR3-4D and TaBOR3-7B were upregulated by low and high B concentrations, respectively, but had expression only in roots. Our results provide basic information on the TaBOR family, which is beneficial for elucidating the functions of TaBOR genes to overcome the problem of B deficiency.

BackgroundsEctopic fat deposition is closely related to chronic kidney disease (CKD). Currently, there are few population studies that have been conducted to determine the relationship between renal parenchyma fat deposition and the risk of CKD among patients with type 2 diabetes mellitus (T2DM). Therefore, we employed magnetic resonance imaging (MRI) to detect renal parenchyma fat content in individuals with T2DM, expressed as renal fat fraction (FF), to explore whether renal FF is an important risk factor for CKD in patients with T2DM.MethodsIn this cross-sectional study, 189 subjects with T2DM were enrolled. CKD was defined as the estimated glomerular filtration rate (eGFR)2. Measurement of the renal FF was performed on a 3.0-T MRI (MAGNETOM Skyra, Siemens, Erlangen, Germany). Binary logistic regression was used to determine the association between tertiles of renal FF and risk of CKD. Receiver-operator characteristic (ROC) curves were constructed to evaluate the sensitivity and specificity of renal FF in detecting CKD in T2DM patients.ResultsThe patients were divided into three groups according to tertiles of the renal FF level (2.498 - 7.434). As renal FF increases, patients tend to be older, and more abdominally obese, with a decreased eGFR (pConclusionsThe renal FF is significantly independently associated with CKD in patients with T2DM.

With the widespread use of advanced imaging technology, adrenal tumors are increasingly being identified.To investigate the prevalence and characteristics of adrenal tumors in an unselected screening population in China.Cross-sectional study. (ClinicalTrials.gov: NCT04682938).A health examination center in China.Adults having an annual checkup were invited to be screened for adrenal tumors by adrenal computed tomography.The participants with adrenal tumors had further evaluation for malignancy risk and adrenal function.A total of 25 356 participants were screened, 351 of whom were found to have adrenal tumors, for a prevalence of 1.4%. The prevalence increased with age, from 0.2% in participants aged 18 to 25 years to 3.2% in those older than 65 years. Among 351 participants with adrenal tumors, 337 were diagnosed with an adrenocortical adenoma, 14 with another benign nodule, and none with a malignant mass. In 212 participants with an adenoma who completed endocrine testing, 69.3% were diagnosed with a nonfunctioning adenoma, 18.9% with cortisol autonomy, 11.8% with primary aldosteronism, and none with pheochromocytoma. Proportions of nonfunctioning adenomas were similarly high in various age groups (72.2%, 67.8%, and 72.2% in those aged46, 46 to 65, and ≥66 years, respectively).Only 212 of 337 participants with an adrenocortical adenoma had endocrine testing.The prevalence of adrenal tumors in the general adult screening population is 1.4%, and most of these tumors are nonfunctioning regardless of patient age. Cortisol and aldosterone secretion are the main causes of functional adenomas.National Key Research and Development Program of China and National Natural Science Foundation of China.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) is a network structure composed of loose chromatin and embedded with multiple proteins. Here, we observed increased NETs deposition in the glomeruli of DKD patients and diabetic mice (streptozotocin-induced or db/db mice). After degrading NETs with DNase I, diabetic mice exhibited attenuated glomerulopathy and glomerular endothelial cells (GECs) injury. We also observed alleviated glomerulopathy and GECs injury in peptidylarginine deiminase 4 (PAD4)-knockout mice with streptozotocin-induced diabetes. In vitro, NET-induced GECs pyroptosis was characterized by pore formation in the cell membrane, dysregulation of multiple genes involved in cell membrane function, and increased expression of pyroptosis-related proteins. Strengthening the GECs surface charge by oleylamine significantly inhibited NETs-induced GECs pyroptosis. These findings suggest that the GECs charge related pyroptosis is involved in DKD progression which promoted by NETs.

Purpose: Adrenal vein sampling (AVS) is the recommended procedure for subtyping primary aldosteronism (PA) as unilateral PA (UPA) or bilateral PA (BPA) which needs adrenalectomy and medication treatment, respectively. However, AVS is invasive and technically difficult. How to subtype PA non-invasively is currently a great challenge. We aimed to prospectively evaluate the accuracy of 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT) in subtyping PA, using AVS as a reference standard.Methods: Patients diagnosed with PA were recruited to undergo AVS and 68Ga-Pentixafor PET/CT. Maximum standardized uptake value (SUVmax) of each adrenal during the PET/CT was measured to calculate the lateralization index (LI) of SUVmax. Area under the receiver operating characteristic curve (AUC), specificity and sensitivity were used to analyze the accuracy of LI based on SUVmax for subtyping PA.Results: One hundred PA patients completed the study, including 43 UPA and 57 BPA. SUVmax of adrenals at 10min during the PET/CT positively correlated with aldosterone concentration (r=0.27, P=0.0001) as well as aldosterone-cortisol ratio (r=0.38, PConclusions: 68Ga-Pentixafor PET/CT is a promising subtyping method for PA with high diagnostic accuracy. For a large proportion of PA patients, 68Ga-Pentixafor PET/CT could be used to avoid invasive AVS.Trial registration number：ClinicalTrials.gov: NCT 05131061. Registered 10 November 2021.

It is significant for anesthesiologists to have a precise grasp of the recovery time of the patient after anesthesia. Accurate prediction of anesthesia recovery time can support anesthesiologist decision-making during surgery to help reduce the risk of surgery in patients. However, effective models are not proposed to solve this problem for anesthesiologists. In this paper, we seek to find effective forecasting methods. First, we collect 1824 patient anesthesia data from the eye center and then performed data preprocessing. We extracted 85 variables to predict recovery time from anesthesia. Second, we extract anesthesia information between variables for prediction using machine learning methods, including Bayesian ridge, lightGBM, random forest, support vector regression, and extreme gradient boosting. We also design simple deep learning models as prediction models, including linear residual neural networks and jumping knowledge linear neural networks. Lastly, we perform a comparative experiment of the above methods on the dataset. The experiment demonstrates that the machine learning method performs better than the deep learning model mentioned above on a small number of samples. We find random forest and XGBoost are more efficient than other methods to extract information between variables on postoperative anesthesia recovery time.

TiO2 films exhibiting structural colors were successfully prepared using one-step electrochemical oxidation. Results of theoretical analyses and digital simulations revealed that the structural color of a TiO2 thin film could be regulated by adjusting oxidation voltage and oxidation time with different oxidation voltages leading to changes in structural color annulus number. At a low oxidation voltage, each thin film exhibited a single structural color, while thin films with different structural colors were obtained by varying the oxidation time. By contrast, at a higher oxidation voltage, each film exhibited iridescent and circular structural color patterns associated with symmetrical decreases in surface oxidation current density along radial lines emanating from the film center to its outer edges. TiO2 films exhibiting iridescent structural colorations have broad application prospects in industrial fields related to photocatalysis and photovoltaic cells.

Boron (B) deficiency is an agricultural problem that causes significant yield losses in many countries. B transporters (

In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17-28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel. We also showed in in vitro and in vivo experiments that TP-CH-1178, a membrane-permeable polypeptide against the NAC1 NES motif, blocked the nuclear export of NAC1, interfered with the degradation of cyclin B1 and sensitized ovarian cancer cells to docetaxel. This study not only reveals a novel mechanism by which the NAC1 nuclear export is regulated and cyclin B1 degradation and mitotic exit are impacted by the NAC1-Cul3 complex, but also provides the nuclear-export pathway of NAC1 as a potential target for modulating taxanes resistance in ovarian cancer and other malignancies.

Indium tin oxide (ITO) targets possess good performances, thereby used to produce high-quality ITO films in transparent electrodes of various optoelectronic devices. The performance of the target greatly affects the performances of prepared ITO films. However, effect of the overall performance of ITO targets on ITO films performance is still not fully understood. ITO films were prepared with four targets by magnetron sputtering in the similar condition in this study. Effects of crystal structure, resistivity, and oxygen content of the targets on photoelectric performances of ITO films were all evaluated. Results showed the important effect of target properties on obtained film characteristics. ITO films prepared by low resistivity targets are more evenly distributed on the substrate surface. Meanwhile, oxygen content of obtained ITO films decreased as oxygen content of ITO targets used in sputtering process increased. This also significantly improved the photoelectric performances. ITO thin films deposited using targets with low resistivity and low oxygen content exhibited excellent photoelectric performances. In this experiment, the prepared ITO film illustrated the lowest resistivity of 1.75×10−4 Ω·cm and average transmittance of 90.5%. In sum, these findings provided a certain experimental basis for further improving the performances of ITO films.

Moso bamboo (Phyllostachys edulis), an apt example of an anisotropic, functionally graded composite material, is the most important commercial bamboo species of China. This species has excellent mechanical properties due to its unique vascular bundle structure. This article examines the variation in mechanical properties of single vascular bundles with respect to their location within a bamboo culm. The mechanical exfoliation method was used to prepare the single vascular bundle. This study found that moso bamboo has superior stiffness and strength. Additionally, the variation in properties was large in the radial direction but minimal in longitudinal direction. The large variation in mechanical properties of vascular bundles can be ascribed to the synergistic effect of the fibrous sheath and parenchyma rather than to changes in fibrous sheath properties. This study provides a basis for the structure application for moso bamboo.

Objective The saline suppression test (SST) and captopril challenge test (CCT) are commonly used confirmatory tests for primary aldosteronism (PA). Seated SST (SSST) has been reported to be superior to recumbent SST. Whether SSST is better than CCT remains unclear. We aimed to compare the diagnostic accuracy of SSST and CCT in a prospective study. Methods Hypertensive patients at a high risk of PA were consecutively included. Patients with an aldosterone-renin ratio of ≥1.0 ng/dL/μIU/mL were asked to complete SSST, CCT, and the fludrocortisone suppression test (FST). Using FST as a reference standard (plasma aldosterone concentration [PAC] post FST ≥ 6.0 ng/dL), area under the receiver-operating characteristic curve (AUC), sensitivity, and specificity of SSST and CCT were calculated, and multiple regression analyses were performed to identify potential factors leading to false diagnosis. Results A total of 196 patients diagnosed with PA and 73 with essential hypertension completed the study. Using PAC post SSST and PAC post CCT to confirm PA, SSST and CCT had comparable AUCs (AUCSSST 0.87 [95% CI 0.82-0.91] vs AUCCCT 0.88 [0.83-0.95], P = .646). When PAC post SSST and post CCT were set at 8.5 and 11 ng/dL, respectively, the sensitivity and specificity of SSST (0.72 [0.65, 0.78] and 0.86 [0.76, 0.93]) and CCT (0.73 [0.67, 0.80] and 0.85 [0.75, 0.92]) were not significantly different. In the multiple regression analyses, 1-SD increment of sodium intake resulted in a 40% lower risk of false diagnosis with SSST. Conclusion SSST and CCT have comparable diagnostic accuracy. Insufficient sodium intake decreases the diagnostic efficiency of SSST but not of CCT. Since CCT is simpler and cheaper, it is preferred over SSST.

Background and ObjectivesThe study aimed to evaluate the performance of a predictive model using the kidney failure risk equation (KFRE) for end-stage renal disease (ESRD) in diabetes and to investigate the impact of glomerular filtration rate (GFR) as estimated by different equations on the performance of the KFRE model in diabetes.Design, Setting, Participants, and MeasurementsA total of 18,928 individuals with diabetes without ESRD history from the UK Biobank, a prospective cohort study initiated in 2006–2010, were included in this study. Modification of diet in renal disease (MDRD), chronic kidney disease epidemiology collaboration (CKD-EPI) or revised Lund–Malmö (r-LM) were used to estimate GFR in the KFRE model. Cox proportional risk regression was used to determine the correlation coefficients between each variable and ESRD risk in each model. Harrell’s C-index and net reclassification improvement (NRI) index were used to evaluate the differentiation of the models. Analysis was repeated in subgroups based on albuminuria and hemoglobin A1C (HbA1c) levels.ResultsOverall, 132 of the 18,928 patients developed ESRD after a median follow-up of 12 years. The Harrell’s C-index based on GFR estimated by CKD-EPI, MDRD, and r-LM was 0.914 (95% CI = 0.8812–0.9459), 0.908 (95% CI = 0.8727–0.9423), and 0.917 (95% CI = 0.8837–0.9496), respectively. Subgroup analysis revealed that in diabetic patients with macroalbuminuria, the KFRE model based on GFR estimated by r-LM (KFRE-eGFRr-LM) had better differentiation compared to the KFRE model based on GFR estimated by CKD-EPI (KFRE-eGFRCKD-EPI) with a KFRE-eGFRr-LM C-index of 0.846 (95% CI = 0.797–0.894, p = 0.025), while the KFRE model based on GFR estimated by MDRD (KFRE-eGFRMDRD) showed no significant difference compared to the KFRE-eGFRCKD-EPI (KFRE-eGFRMDRD C-index of 0.837, 95% CI = 0.785–0.889, p = 0.765). Subgroup analysis of poor glycemic control (HbA1c >8.5%) demonstrated the same trend. Compared to KFRE-eGFRCKD-EPI (C-index = 0.925, 95% CI = 0.874–0.976), KFRE-eGFRr-LM had a C-index of 0.935 (95% CI = 0.888–0.982, p = 0.071), and KFRE-eGFRMDRD had a C-index of 0.925 (95% CI = 0.874–0.976, p = 0.498).ConclusionsIn adults with diabetes, the r-LM equation performs better than the CKD-EPI and MDRD equations in the KFRE model for predicting ESRD, especially for those with macroalbuminuria and poor glycemic control (HbA1c >8.5%).

The association between fat mass and mortality has been equivocally shown to be linear, J-shaped, and U-shaped. We aimed to clarify this relationship based on Mendelian randomization (MR) analysis and lifestyle modification.This prospective analysis included 449,831 participants from UK Biobank. Linear MR analysis was used to estimate the linear relationship between fat mass and mortality. We assessed whole body fat mass by bioimpedance analysis at baseline and categorized subjects into five equal groups based on fat mass index (FMI). The association between FMI and mortality were investigated among whole population and in subgroups stratified by individual lifestyle factors, including diet, physical activity, smoking, alcohol, sleep and psychological health.Linear MR analyses indicated a positive association between genetically predicted fat mass and all-cause mortality (HR 1.10, 95 % CI 1.08-1.12, P 0.001). The association between FMI and all-cause mortality was manifested as J-shaped (HRs across FMI categories: 1.04, 1.00, 1.07, 1.21, 1.54), which was significantly modified by the number of low-risk lifestyle factors (P for interaction0.001). When evaluating individual lifestyle factors, we observed a nonlinear relationship between FMI and all-cause mortality among participants who had high-risk lifestyle factors, while a linear relationship was observed among participants who had low-risk lifestyle factors, especially for those with adequate physical activity (HRs across FMI categories: 0.95, 1.00, 1.05, 1.17, 1.44) and who never smoked (0.96, 1.00, 1.03, 1.14, 1.51).Genetically determined fat mass is causally and linearly associated with mortality. The J-shape association between anthropometric FMI and mortality is caused by high-risk lifestyle factors.

Overlapping coding regions balance selective forces between multiple genes. One possible division of nucleotide sequence is that the predominant selective force on a particular nucleotide can be attributed to just one gene. While this arrangement has been observed in regions in which one gene is structured and the other is disordered, we sought to explore how overlapping genes balance constraints when both protein products are structured over the same sequence. We use a combination of sequence analysis, functional assays, and selection experiments to examine an overlapped region in HIV-1 that encodes helical regions in both Env and Rev. We find that functional segregation occurs even in this overlap, with each protein spacing its functional residues in a manner that allows a mutable non-binding face of one helix to encode important functional residues on a charged face in the other helix. Additionally, our experiments reveal novel and critical functional residues in Env and have implications for the therapeutic targeting of HIV-1.

Microorganisms play a key role in ruminal digestion, some of which can be used as probiotics to promote growth in ruminants. However, which potential bacteria are responsible for ruminant growth and how they potentiate the basic mechanism is unclear. In this study, three bacterial strains, Bacillus pumilus (SN-3), Bacillus paralicheniformis (SN-6), and Bacillus altitudinis (SN-20) with multiple digestive enzymes were isolated from the rumen of healthy buffaloes. Among these strains, SN-6 secreted cellulase, laccase, and amylase, and significantly inhibited Staphylococcus aureus ATCC25923 and Escherichia coli K99 in vitro. In addition, SN-6 exhibited strong tolerance to artificial gastric juice, intestinal juice, and high temperature. Antibiotic resistance test, virulence gene test, and mouse toxicity test confirmed the safety of SN-6. Further, SN-6 significantly increased the body weight (p < 0.01), affects the intestinal microbiota structure, and alters the metabolomic patterns of Simmental. There was a remarkable difference in the β diversity of fecal microflora between SN-6 and control groups (p < 0.05). Furthermore, SN-6 significantly increased the abundance of Clostridium_sensu_stricto_1, Bifidobacterium, Blautia, and Cellulolyticum, decreased the relative abundance of Monoglobus and norank_f_Ruminococcacea. Moreover, SN-6 feeding significantly enriched intestinal metabolites (i.e., 3-indoleacrylic acid, kynurenic acid) to maintain intestinal homeostasis. Finally, the microbial and metabolic functional analysis indicated that SN-6 could enhance amino acid metabolism (mainly tryptophan metabolism) and lipid metabolism pathways. Overall, these findings indicated that SN-6 could be used as a probiotic in ruminants.

Background: Microorganisms play a key role in rumen digestion which are often used as probiotics to promote growth in ruminants. However, it's unclear which bacteria play an important role and how they do it. This study focused on the growth-promoting effects of the buffalo-derived probiotic SN-6 and examined its effects on the fecal flora and metabolism in Simmental, analyzing the impact of altered intestinal flora on host metabolism to elucidate the underlying probiotic mechanisms.Results: Three bacterial strains, Bacillus pumilus (SN-3), Bacillus paralicheniformis (SN-6) and Bacillus altitudinis (SN-20) with multiple digestive enzymes secretion capability were isolated from the rumen of healthy Buffalo, SN-6 exhibited outstanding among the three strains. SN-6 secreted cellulase, laccase and amylase, and had potent inhibitory effects on Staphylococcus aureus ATCC25923 and Escherichia coli K99. In addition, SN-6 exhibited strong tolerance to artificial gastric juice, intestinal juice and high temperature. Antibiotic resistance test, virulence gene test and mouse toxicity test confirmed the safety of SN-6. SN-6 significantly increased the average daily weight gain of Simmental (pClostridium_sensu_stricto_1, Bifidobacterium, Blautia and Cellulolyticum and decreased the relative abundance of Monoglobus, norank_f_Ruminococcacea. Moreover, SN-6 feeding significantly enriched fecal metabolites to maintain intestinal homeostasis and strengthen intestinal barrier function (i.e., 3-Indoleacrylic acid, Kynurenic acid). Finally, the microbial and metabolic function analysis indicated that SN-6 would enhance amino acid metabolism (mainly tryptophan metabolism) and lipid metabolism pathways.Conclusions: SN-6 exerted beneficial effects by targeting the gut microbiota and host metabolism (mainly tryptophan metabolism). Our findings reveal the effect of SN-6 on Simmental microbiota and metabolism, and provide a new reference for the research on Bacillus regulating ruminant gut microbiota and metabolism.

Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic kidney disease (DKD). Our previous studies demonstrated that puerarin, the active compound of radix puerariae, improves podocyte injury in type 1 DKD mice. However, the direct molecular target of puerarin and its underlying mechanisms in DKD remain unknown. In this study, we confirmed that puerarin also improved DKD in type 2 diabetic db/db mice. Through RNA-sequencing odf isolated glomeruli, we found that differentially expressed genes (DEGs) that were altered in the glomeruli of these diabetic mice but reversed by puerarin treatment were involved mostly in oxidative stress, inflammatory and fibrosis. Further analysis of these reversed DEGs revealed protein kinase A (PKA) was among the top pathways. By utilizing the drug affinity responsive target stability method combined with mass spectrometry analysis, we identified guanine nucleotide-binding protein Gi alpha-1 (Gnai1) as the direct binding partner of puerarin. Gnai1 is an inhibitor of cAMP production which is known to have protection against podocyte injury. In vitro, we showed that puerarin not only interacted with Gnai1 but also increased cAMP production in human podocytes and mouse diabetic kidney in vivo. Puerarin also enhanced CREB phosphorylation, a downstream transcription factor of cAMP/PKA. Overexpression of CREB reduced high glucose-induced podocyte apoptosis. Inhibition of PKA by Rp-cAMP also diminished the effects of puerarin on high glucose-induced podocyte apoptosis. We conclude that the renal protective effects of puerarin are likely through inhibiting Gnai1 to activate cAMP/PKA/CREB pathway in podocytes.

BackgroundIndividual lifestyle varies in the real world, and the comparative efficacy of lifestyles to preserve renal function remains indeterminate. We aimed to systematically compare the effects of lifestyles on chronic kidney disease (CKD) incidence, and establish a lifestyle scoring system for CKD risk identification.MethodsUsing the data of the UK Biobank cohort, we included 470,778 participants who were free of CKD at the baseline. We harnessed the light gradient boosting machine algorithm to rank the importance of 37 lifestyle factors (such as dietary patterns, physical activity (PA), sleep, psychological health, smoking, and alcohol) on the risk of CKD. The lifestyle score was calculated by a combination of machine learning and the Cox proportional-hazards model. A CKD event was defined as an estimated glomerular filtration rate 2, mortality and hospitalization due to chronic renal failure, and self-reported chronic renal failure, initiated renal replacement therapy.ResultsDuring a median of the 11-year follow-up, 13,555 participants developed the CKD event. Bread, walking time, moderate activity, and vigorous activity ranked as the top four risk factors of CKD. A healthy lifestyle mainly consisted of whole grain bread, walking, moderate physical activity, oat cereal, and muesli, which have scored 12, 12, 10, 7, and 7, respectively. An unhealthy lifestyle mainly included white bread, tea >4 cups/day, biscuit cereal, low drink temperature, and processed meat, which have scored −12, −9, −7, −4, and −3, respectively. In restricted cubic spline regression analysis, a higher lifestyle score was associated with a lower risk of CKD event (p for linear relation < 0.001). Compared to participants with the lifestyle score < 0, participants scoring 0–20, 20–40, 40–60, and >60 exhibited 25, 42, 55, and 70% lower risk of CKD event, respectively. The C-statistic of the age-adjusted lifestyle score for predicting CKD events was 0.710 (0.703–0.718).ConclusionA lifestyle scoring system for CKD prevention was established. Based on the system, individuals could flexibly choose healthy lifestyles and avoid unhealthy lifestyles to prevent CKD.

Neutrophil-related chronic inflammation (NRCI) may contribute to the pathogenesis of diabetic kidney disease (DKD). We evaluated whether blocking NRCI with low-dose colchicine prevents DKD.A double-blind, randomized, placebo-controlled study was conducted. A total of 160 patients with type 2 diabetes (T2D) and microalbuminuria (urinary albumin creatinine ratio [UACR] 30 to 300 mg/g Cr) who received angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) for at least 3 months were included. Subjects were 1:1 randomized to a placebo or colchicine group (0.5 mg/day).The primary end point was the incidence of overt nephropathy (UACR 300 mg/g Cr). During the 36 months, 38 patients (51.4%) in colchicine group and 39 (54.1%) in the control group developed overt nephropathy (hazard ratio, 1.066; 95% confidence interval, 0.679-1.673; P = .78). Compared with placebo, colchicine modestly lowered levels of NRCI parameters (P values.05 for high-sensitivity C-reactive protein, white blood cell counts, neutrophil counts, and neutrophil-to-lymphocyte ratio), whereas the changes of UACR and estimated glomerular filtration rate (eGFR) were similar between the two groups. There were no significant differences between the two groups in drug-related adverse events, including infection, gastrointestinal symptoms, and limb numbness.In patients with T2D with microalbuminuria, low-dose colchicine effectively and safely lowered NRCI but did not prevent the incidence of overt nephropathy.背景: 中性粒细胞相关性慢性炎症(NRCI)可能与糖尿病肾病(DKD)的发生有关。我们用低剂量秋水仙碱抑制NRCI并评估其是否能延缓DKD的发生。 方法: 本研究为一项双盲、随机、安慰剂对照临床试验。研究共纳入2型糖尿病合并微量白蛋白尿(肌酐比 [UACR] 30-300mg/g Cr)的患者共160名, 所有患者均接受血管紧张素转换酶抑制剂(ACEi)或血管紧张素受体拮抗剂(ARBs)类药物至少3个月。患者按1:1随机分为安慰剂组或秋水仙碱组(接受秋水仙碱0.5mg/d)。 结果: 本研究的主要终点为显著肾病(UACR300mg/g Cr)的发生率。在随访的36个月中, 秋水仙碱组的38名患者(51.4%)以及安慰剂组的39名患者(54.1%)发展成为了显著肾病(危险比1.066; 95%置信区间 0.679-1.673; p=0.78)。秋水仙碱组与安慰剂组相比, NRCI水平有所下降(高灵敏C-反应蛋白、白细胞总数、中性粒细胞总数、中性粒细胞-淋巴细胞比值等指标, 两组有显著性差异, p0.05), 但两组的UACR变化率、估算肾小球滤过率变化率无显著差异。两组的药物相关不良反应, 包括感染、胃肠道症状、肢体麻木等症状无显著差异。 结论: 在2型糖尿病合并微量白蛋白尿的患者中, 低剂量秋水仙碱能有效且安全地降低NRCI, 但是不能延缓DKD的发生。.

To achieve high mechanical strength electromagnetic interference (EMI) shielding materials for practical application, cellulose nanocrystals (CNC), as a reinforcing and dispersing agent, are intercalated into reduced graphene oxide (RGO) layers, forming an ultrathin, robust, flexible, and hydrophobic CNC/RGO film with a highly ordered nacre-like layered structure via a self-assembly process. The layered structure significantly shortens the reduction time and improves the mechanical strength and shielding effectiveness (SE) of the resultant CNC/RGO composite film. The controlled preparation of CNC with different aspect ratios is realized by using separated bamboo fiber and parenchyma. The CNC of the fiber with a higher aspect ratio and lower diameter results in a lower porosity, denser structure, and more uniform distribution in the composites, and therefore a higher electrical conductivity and SE. The highest SE (39.1 dB) and specific SE (11 367 dB cm2 g−1) with a high tensile strength (179 MPa) and water contact angle (106°) of the CNC/RGO film are obtained at 10 wt% CNC loading with a film thickness of 12 μm. The maximum tensile strength of the composite film reaches 227 MPa with 30–50% CNC. The ultrathin high-performance CNC/RGO film shows significant potential as an EMI shielding material in the aerospace and flexible electronics fields.